There have been studies on a strategy for treating neurodegenerative diseases, in particular dementia (including Alzheimer's disease), where a nuclear receptor is targeted. For example, an agonist to a PPAR (peroxisome proliferator-activated receptor) has been described to be effective for treating dementia. It has been described that bexarotene which is a full agonist targeting a retinoid X receptor (RXR) is effective for treating dementia.
Bexarotene has been used a therapeutic agent for cutaneous invasive T-cell lymphoma in many countries including the United States and Japan, and has been reported to have an effect for treating type II diabetes, a therapeutic effect in an Alzheimer's disease model mouse and an effect for treating Parkinson's disease. However, conventional RXR agonists including bexarotene have a problem of side effects such as decreased thyroid activity, enlargement of the liver, weight gain and elevation of blood triglyceride level. Any RXR agonist having such a problem of side effects is a full agonist which can fully activate a RXR.
We have hypothesized that there is a difference between a threshold of drug efficacy by an RXR agonist and a threshold of expression of side effects such as enlargement of the liver. We have further supposed that a partial agonist whose activation ability (efficacy) is reduced in comparison with an RXR full agonist could exhibit drug efficacy capable of improving not only insulin resistance but also glucose tolerance as a sole drug while avoiding side effects. As a result of study, we have found that RXR partial agonists which we have created exhibit potent antihyperglycemic action and improvement in insulin resistance while reducing side effects as a conventional problem associated with an RXR full agonist. Molecular structures of typical RXR partial agonists which we have created are as follows (see Patent Reference Nos. 1 to 4).

Each of these compounds was orally administered to mice at a dose of 30 mg/kg/day for one week, and body weight change over a week and also enlargement of the liver and elevation of blood triglyceride level as a problem for an RXR full agonist were determined. As a result, tendency to weight gain was not observed in groups treated with CBt-PMN or NEt-4IB as an RXR partial agonist. Furthermore, for a liver weight and a triglyceride level, there was not a difference between the CBt-PMN or NEt-4IB group and a vehicle group. Furthermore, although these compounds were orally repeatedly administered to male and female rats at a dose of 30 mg/kg/day repeatedly for 28 days, no significant differences in weight change, water intake and food intake were observed, compared with a vehicle treatment group (see Non-patent Reference Nos. 1 to 3).